BCG026：FAP × GPC1双特异性ADC——一种针对胰腺癌及其他实体瘤中基质细胞和肿瘤细胞的新型靶向策略

Background Pancreatic adenocarcinoma (PAAD) is a highly aggressive cancer that urgently needs new therapeutic strategies. Characterized by a dense fibrotic and desmoplastic stroma, PAAD leads to rapid disease progression, treatment resistance, and poor clinical outcomes. The primary components of this stroma are cancer-associated fibroblasts (CAFs), which accumulate within the tumor and increase the expression of collagen and fibronectin, thereby remodeling the extracellular matrix. CAFs also facilitate the desmoplastic response, contributing to early invasion, high recurrence rates, and resistance to treatment in PAAD. As a result, CAFs represent a promising therapeutic target not only in PAAD but also in other solid tumors. Fibroblast activation protein (FAP) is selectively expressed by CAFs in the majority of human epithelial cancers. Glypican 1 (GPC-1) is aberrantly expressed and plays a significant role in various cancers. It is notably increased in PAAD and has also been found at elevated levels in colorectal, prostate, and breast cancers. We have confirmed that the PAAD tissue microarray (TMA) showed high expression levels of both FAP and GPC1. In response, we developed BCG026, a novel bispecific ADC that targets both stromal and tumor cells. This approach aims to deplete the tumor stroma, thereby improving efficacy against the stroma barrier and tumor heterogeneity, as well as overcoming resistance associated with traditional single-target therapies. A fully human bispecific antibody against FAP and GPC1 was generated using Biocytogen's RenLite ® transgenic mice. The bsAb backbone demonstrated high affinity for both FAP and GPC1, effectively binding to a diverse panel of tumor cells. Results Furthermore, it exhibited robust binding activity in both stromal and tumor cells, regardless of their varying expression levels of FAP and GPC1. Notably, the bsAb also showed efficient internalization in both stromal and tumor cells, indicating its capacity to deliver therapeutic payloads effectively to stroma and tumor cells. We then conjugated the bsAb with TOP1i linker-payload (BLD1102) to create BCG026. This novel bsADC exhibited a CAF-dependent bystander killing effect in vitro , suggesting its ability to induce cytotoxicity in FAP-positive stroma and tumor cells that may not express the target antigens, but are present in proximity to CAFs. Furthermore, BCG026 demonstrated potent efficacy in pancreatic and lung cancer PDX models, as well as a superior synergistic effect to that of the parent ADCs in certain models. Conclusion These findings underscore its significant potential as a powerful therapeutic agent for targeting PAAD and other tumors. Further preclinical studies are currently underway.